Process for the racemization of chiral quinazolinones

ABSTRACT

Racemates are obtained from one of the enantiomers, or an enantiomerically enriched mixture, of an optically active quinazolinone derivative by reaction of the compound with an alkali alkoxide of a primary alcohol and isolation of the racemate.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S.Ser. No. 60/332,148, filed Nov. 20, 2002, which is incorporated byreference in its entirety for all purposes.

FIELD OF THE INVENTION

[0002] This invention relates to a process for racemizing one of theenantiomers, or an enantiomerically enriched mixture, of an opticallyactive compound. This invention more specifically relates toracemization of quinazolinone derivatives.

BACKGROUND OF THE INVENTION

[0003] Interest in the medicinal chemistry of quinazoline derivativeswas stimulated in the early 1950's with the elucidation of the structureof a quinazoline alkaloid,3-[β-keto-γ-(3-hydroxy-2-piperidyl)-propyl]-4-quinazolone, from an Asianplant known for its antimalarial properties. In a quest to findadditional antimalarial agents, various substituted quinazolines havebeen synthesized. Of particular import was the synthesis of thederivative 2-methyl-3-o-tolyl-4-(3H)-quinazolinone. This compound, knownby the name methaqualone, though ineffective against protozoa, was foundto be a potent hypnotic.

[0004] Since the introduction of methaqualone and its discovery as ahypnotic, the pharmacological activity of quinazolinones and relatedcompounds has been investigated. Quinazolinones and derivatives thereofare now known to have a wide variety of biological properties includinghypnotic, sedative, analgesic, anticonvulsant, antitussive andanti-inflammatory activities.

[0005] Quinazolinones are among a growing number of therapeutic agentsused to treat cell proliferative disorders, including cancer. Forexample, PCT WO 01/30768, which is incorporated herein by reference inits entirety, describes a pharmaceutical composition containingquinazolinone derivatives which are inhibitors of the mitotic kinesinKSP and are useful in the treatment of cellular proliferative diseases,for example cancer, hyperplasias, restenosis, cardiac hypertrophy,immune disorders and inflammation. Certain of the compounds describedtherein have the following formula:

[0006] wherein

[0007] R₁ is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, and substituted heteroaralkyl;

[0008] R₂ and R₂′ are independently chosen from hydrogen, alkyl,oxaalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl,substituted aryl, substituted aralkyl, substituted heteroaryl, andsubstituted heteroaralkyl; or R₂ and R₂′ taken together form a 3- to7-membered ring;

[0009] R₃ is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, substituted heteroaralkyl, oxaalkyl, oxaaralkyl,substituted oxaaralkyl, R₁₅O— and R₁₅—NH—;

[0010] R_(3a) is chosen from hydrogen, alkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl,substituted alkylaryl, substituted heteroaryl, substitutedalkylheteroaryl and R₁₅—NH—;

[0011] R_(3b) is chosen from alkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, substituted alkyl, substituted aryl, substitutedalkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

[0012] R₄ is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, substituted heteroaralkyl, and R₁₆-alkylene-;

[0013] R₅, R₆, R₇ and R₈ are independently chosen from hydrogen, alkyl,alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl,alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio,carboxyalkyl, carboxamido, aminocarbonyl, aryl and heretoaryl;

[0014] R₁₅ is chosen from alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, and substituted heteroaralkyl; and

[0015] R₁₆ is chosen from alkoxy, amino, alkylamino, dialkylamino,N-heterocyclyl and substituted N-heterocyclyl.

[0016] These quinazolinone derivatives have an asymmetric carbon atom(i.e., the stereogenic center to which R₂ and R₂ are attached) that mayexist as a racemic mixture of these compounds, i.e., a mixture of boththe (+) and (−) or dextro and levo rotary forms. These compounds can beproduced as racemates and administered in this form. However, it isknown that the physiological utility of racemic mixtures often isfocused on one enantiomer, the other having either little or no effector even diminishing the effect of the active enantiomer.

[0017] A generic synthetic scheme for the preparation of quinazolinonecompounds of Formula I(a)-(d) above is described in PCT WO 01/30768 andis shown in FIGS. 1 and 2. An asymmetric synthesis of the quinazolinonecompounds of Formula I using optically active reagents is shown in FIG.3. Disposal of the undesired enantiomer of an intermediate is notenvironmentally or economically desirable. Thus an efficient method ofconverting the inactive or undesirable enantiomer into the other usable,desirable enantiomer is a commercially important objective. Thisinvention makes it possible to achieve this objective.

[0018] The references discussed herein are provided solely for theirdisclosure prior to the filing date of the present application and areeach incorporated herein by reference. Nothing herein is to be construedas an admission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention.

SUMMARY OF THE INVENTION

[0019] The present invention provides a method for racemizing one of theenantiomers, or an enantiomerically enriched mixture, of an opticallyactive compound of the formula:

[0020] comprising:

[0021] contacting said compound with an alkali alkoxide of a C₁-C₆primary alcohol; and

[0022] isolating the resulting racemic compound,

[0023] wherein

[0024] R₁ is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, and substituted heteroaralkyl;

[0025] R₂ is alkyl, oxaalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,substituted alkyl, substituted aryl, substituted aralkyl, substitutedheteroaryl, and substituted heteroaralkyl; and

[0026] R₅, R₆, R₇ and R₈ are independently chosen from hydrogen, alkyl,alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl,alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio,carboxyalkyl, carboxamido, aminocarbonyl, aryl and heretoaryl.

[0027] The process is characterized in that one of the enantiomers, oran enantiomerically enriched mixture, of enantiomers is contacted withan alkali metal alkoxide of a primary alcohol. Preferably, the reactionmixture comprises the primary alcohol from which the alkali metalalkoxide was derived. The racemic compounds can then be isolated byconventional methods.

[0028] The alkali metal alkoxide of a primary alcohol will generally bederived from a. primary aliphatic alcohol with 1-6 C-atoms, preferablymethanol or ethanol, and more preferably, ethanol. Preferably, thereaction is carried out under reflux temperature.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] This invention will be better understood by reference to thefollowing drawings and description, in which the same reference numeralsare used to identify like components.

[0030]FIG. 1 depicts a generic synthetic scheme to make quinazolinonederivatives of Formula I.

[0031]FIG. 2 depicts a synthetic route for the synthesis ofquinazolinone derivative

[0032]FIG. 3 depicts a synthetic route to substantially pure singleenantiomers.

[0033]FIG. 4 depicts a method for the racemization of quinazolinonederivatives according to one embodiment of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

[0034] General

[0035] Before the present methods are described, it is understood thatthis invention is not limited to the particular methodology, protocols,and reagents described, as these may vary. It is also to he understoodthat the terminology used herein is for the purpose of describingparticular embodiments only and is not intended to limit the scope ofthe present invention which will be limited only by the appended claims.

[0036] It must be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise.

[0037] Unless defined otherwise, all technical and scientific terms usedherein have the same meanings as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, the preferredmethods, devices, and materials are now described.

[0038] Alkyl is intended to include linear, branched, or cyclichydrocarbon structures and combinations thereof. Lower alkyl refers toalkyl groups of from 1 to 5 carbon atoms. Examples of lower alkyl groupsinclude methyl, ethyl, pro pyl, isopropyl, butyl, s-and t-butyl and thelike. Preferred alkyl groups are those of C₂₀ or below. More preferredalkyl groups are those of C₁₃ or below. Cycloalkyl is a subset of alkyland includes cyclic hydrocarbon groups of from 3 to 13 carbon atoms.Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl,norbomyl, and the like. In this application, alkyl refers to alkanyl,alkenyl and alkynyl residues; it is intended to includecyclohexylmethyl, vinyl, allyl, isoprenyl and the like. Alkylene refersto the same residues as alkyl, but having two points of attachment.Examples of alkylene include ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), dimethylpropylene (—CH₂C(CH₃)₂CH₂—) andcyclohexylpropylene (—CH₂CH₂CH(C₆H₁₃)—). When an alkyl residue having aspecific number of carbons is named, all geometric isomers having thatnumber of carbons are intended to be encompassed; thus, for example,“butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl;“propyl” includes n-propyl and isopropyl.

[0039] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms ofa straight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

[0040] Aryl and heteroaryl mean a 5- or 6-membered aromatic orheteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S;a bicyclic 9- or 10-membered aromatic or heteroaromatic ring systemcontaining 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13-or 14-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S. The aromatic 6- to 14-memberedcarbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin,and the 5- to 10-membered aromatic heterocyclic rings include, e.g.,imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan,benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

[0041] Aralkyl refers to a residue in which an aryl moiety is attachedto the parent structure via an alkyl residue. Examples are benzyl,phenethyl, phenylvinyl, phenylallyl and the like. Oxaalkyl andoxaaralkyl refer to alkyl and aralkyl residues in which one or moremethylenes have been replaced by oxygen. Examples of oxaalkyl andoxaaralkyl residues are ethoxyethoxyethyl (3,6-dioxaoctyl),benzyloxymethyl and phenoxymethyl; in general, glycol ethers, such aspolyethyleneglycol, are intended to be encompassed by this group.

[0042] Heteroaralkyl refers to a residue in which a heteroaryl moiety isattached to the parent structure via an alkyl residue. Examples includefuranylmethyl, pyridinylmethyl, pyrimidinylethyl and the like.

[0043] Heterocycle means a cycloalkyl or aryl residue in which one tofour of the carbons is replaced by a heteroatom such as oxygen, nitrogenor sulfur. Examples of heterocycles that fall within the scope of theinvention include imidazoline, pyrrolidine, pyrazole, pyrrole, indole,quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran,benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl,when occurring as a substituent), tetrazole, morpholine, thiazole,pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline,isoxazole, dioxane, tetrahydrofuran and the like. “N-heterocyclyl”refers to a nitrogen-containing heterocycle as a substituent residue.The term heterocyclyl encompasses heteroaryl, which is a subset ofheterocyclyl. Examples of N-heterocyclyl residues include 4-morpholinyl,4-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 3-thiazolidinyl,piperazinyl and 4-(3,4-dihydrobenzoxazinyl). Examples of substitutedheterocyclyl include 4-methyl-1-piperazinyl and 4-benzyl-1-piperidinyl.

[0044] Substituted alkyl, aryl and heteroaryl refer to alkyl, aryl orheteroaryl wherein H atoms are replaced with alkyl, halogen, hydroxy,alkoxy, alkylenedioxy (e.g. methylenedioxy) fluoroalkyl, carboxy(—COOH), carboalkoxy (i.e. acyloxy RCOO—), carboxyalkyl (—COOR),carboxamido, sulfonamidoalkyl, sulfonamidoaryl, aminocarbonyl,benzyloxycarbonylamino (CBZ-amino), cyano, carbonyl, nitro,dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl,amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy,or heteroaryloxy. For the purposes of the present invention, substitutedalkyl also includes oxaalkyl residues, i.e. alkyl residues in which oneor more carbons has been replaced by oxygen.

[0045] Halogen refers to fluorine, chlorine, bromine or iodine.Fluorine, chlorine and bromine are preferred. Dihaloaryl, dihaloalkyl,trihaloaryl etc. refer to aryl and alkyl substituted with a plurality ofhalogens, but not necessarily a plurality of the same halogen; thus4-chloro-3-fluorophenyl is within the scope of dihaloaryl.

[0046] Starting Materials

[0047] In a preferred embodiment, an enantiomer, or an enantiomericallyenriched mixture, of an optically active compound will have a formula:

[0048] wherein

[0049] R₁ is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, and substituted heteroaralkyl;

[0050] R₂ is alkyl, oxaalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,substituted alkyl, substituted aryl, substituted aralkyl, substitutedheteroaryl, and substituted heteroaralkyl; and

[0051] R₅, R₆, R₇ and R₈ are independently chosen from hydrogen, alkyl,alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl,alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio,carboxyalkyl, carboxamido, aminocarbonyl, aryl and heretoaryl. See, PCTWO 01/30768.

[0052] These compounds contain one or more asymmetric centers (e.g. thecarbon to which R₂ is attached) and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)— or (S)—. The quinazolinonesof Formula II which are enriched in one optical isomer may be used inthe present invention irrespective of the degree of enantiomeric excessof a specific optical isomer contained therein. Thus, the startingmaterial of the racemization method described herein may be enrichedwith the R-configuration or the S-configuration. Preferably, it will beenriched with the S-isomer.

[0053] Preferably, R₁ is selected from hydrogen, alkyl, aryl,substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl,aralkyl, substituted aralkyl, and substituted heteroaralkyl.

[0054] In a more preferred embodiment R₁ is selected from hydrogen,lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyland substituted aralkyl. In a most preferred embodiment R₁ is chosenfrom hydrogen, ethyl, propyl, methoxyethyl, naphthyl, phenyl,bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl,dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl,phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl,tetrahydrofuranylmethyl and (ethoxycarbonyl)ethyl.

[0055] In a preferred embodiment R₂ is alkyl or substituted alkyl. In amost preferred embodiment R₂ is chosen from methyl, ethyl, propyl,methylthioethyl, aminobutyl, (CBZ)aminobutyl, cyclohexylmethyl,benzyloxymethyl, methylsulfinylethyl, methylsulfinylmethyl,hydroxymethyl, benzyl and indolylmethyl.

[0056] Preferably, R₅, R₆, R₇ and R₈ are independently chosen fromhydrogen, halogen, methyl, cyano, and trifluoromethyl. More preferably,R₅ is hydrogen or halogen; R₆, is hydrogen, methyl, or halogen; R₇ ishydrogen, halogen, lower alkyl, substituted lower alkyl, lower alkoxy,or cyano; and/or R₈ is hydrogen or halogen. In another embodiment,embodiment, R₅, R₆, and R₈ are hydrogen. More preferably, R₅, R₆, and R₈are hydrogen and R₇ is halogen

[0057] In a particularly preferred subgenus, R₁ is chosen from aralkylor substituted aralkyl; R₂ is lower alkyl; R₅ is hydrogen; R₆ ishydrogen; R₇ is halo or cyano; and R₈ is hydrogen; or R₁ is benzyl orsubstituted benzyl; R₂ is i-propyl; R₅ is hydrogen; R₆ is hydrogen; R₇is chloro or cyano; and R₈ is hydrogen; or R₁ is benzyl; R₂ is i-propyl;R₅ is hydrogen; R₆ is hydrogen; R₇ is fluoro; and R₈ is hydrogen, or R₁is benzyl; R₂ is i-propyl; R₅ is hydrogen; R₆ is hydrogen; R₇ is chloro;and R₈ is hydrogen; or R₁ is benzyl; R₂ is i-propyl; R₅ is hydrogen; R₆is hydrogen; R₇ is cyano; and R₈ is hydrogen; or R₁ is benzyl orhalobenzyl; R₂ is chosen from ethyl and propyl; R₅ is hydrogen; R₆ ishydrogen; R₇ is halo; and R₈ is hydrogen.

[0058] The Racemization Methods

[0059] In the racemization method of the present invention, racemizationproduces a racemic mixture, which can be separated by conventional meanssuch as column chromatography, optical resolution using an opticallyactive acid and the like.

[0060] The methods of the present invention utilize an alkali alkoxideof a C₁-C₆ primary alcohol to effect the racemization. Preferably, thealkali alkoxide will comprise a sodium or potassium alkoxide. Morepreferably, it will comprise sodium ethoxide.

[0061] The amount of alkali alkoxide used is not particularly limited,but is usually from about 0.01 to 10 moles, preferably 0.01 to 5 moles,more preferably 0.5 to 2 moles per mole of the quinazolinone derivative.Most preferably, equimolar amounts of the alkali alkoxide and thequinazolinone will be used.

[0062] Preferably, a C₁-C₆ primary alcohol will be used as the solvent.More preferably, the solvent will comprise the alcohol from which thealkali alkoxide was derived. Most preferably, the primary alcohol willbe methanol or ethanol. Preferably, the racemization reaction will beconducted in anhydrous conditions.

[0063] The reaction mixture may comprise lesser amounts of other solventincluding aromatic compounds such as benzene, toluene, ethyl benzene,xylene, and chlorobenzene; hydrocarbons such as hexane, cyclohexane,heptane and isooctane; ethers such as t-butyl methyl ether, isopropylether, tetrahydrofuran and dioxane, and mixtures thereof.

[0064] The concentration of starting material in the racemizationreaction may be varied. In general, the reaction will be conducted at aconcentration of about 0.1 to about 5 molar, more preferably at about0.5 to about 2 molar, and most preferably at about 0.5 molar.

[0065] The racemization reaction usually will be conducted at atemperature of less than 200° C.; more preferably, at a temperature ofless than 100° C.; and most preferably, at the reflux (or boiling point)temperature of the reaction mixture.

[0066] The product of the racemization reaction (i.e., the “racemates”)will be less enriched in one optical isomer and thus, will have adecreased degree of enantiomeric excess as compared to the startingmaterial. Preferably, the racemates will be present in about a 1:1ratio.

[0067] The racemized quinazolinone derivative thus obtained by thepresent invention can be reused in an optical resolution process toproduce the desired enantiomer of the optically active quinazolinonederivative after being subjected to a conventional procedure, forexample, hydrolysis or neutralization with acidic water or the like,followed by distillation of the solvent, if necessary.

[0068] Synthesis of Compounds of Formula II

[0069] The compounds of Formula II can be prepared by following theprocedures described with reference to the Reaction Scheme 1 below andby the procedures set forth in the figures and PCT WO 01/30768.

[0070] Preparation of Formula 103

[0071] Referring to Reaction Scheme 1, Step 1, to an optionallysubstituted benzoic acid (the compound of Formula 101) dissolved in aninert organic solvent (such as THF) in the presence of sodiumbicarbonate and a dehydrating agent (such as Na₂SO₄) is added a slightmolar excess of an optionally substituted acid chloride (the compound ofFormula 102), maintaining about room temperature. Completion of thereaction is monitored, e.g., by TLC. Acetic anhydride is then added tothe reaction mixture, which is heated to about 90-100° C., monitoringcompletion of the reaction (e.g., by TLC) followed by removal of theacetic anhydride under vacuum at about 80-100° C. The reaction mixtureis cooled and the corresponding, optionally substitutedbenzo[d][1,3]oxazin-4-one (the compound of Formula 103) is isolated andpurified.

[0072] Preparation of Formula 104

[0073] Referring to Reaction Scheme 1, Step 2, about 1.5 molarequivalents of a primary amine (such as R₁NH₂) and 1 molar equivalent ofa compound of Formula 103 in an inert organic solvent (such as toluene)are heated to reflux. The reaction takes place over a period of 1 to 5hours. After removal of water, ethylene glycol and sodium hydroxide areadded to the reaction mixture and the temperature raised to 110-120° C.Completion of the reaction is monitored, e.g., by TLC. Thecorresponding, optionally substituted quinazolinone (a compound ofFormula 104) is isolated and purified.

[0074] Preparation of Formula 105

[0075] Referring to Reaction Scheme 1, Step 3, a compound of Formula104, dissolved in acetic acid and in the presence of sodium acetate, isheated to 30° C., followed by the addition (with agitation) of a slightmolar excess of bromine in acetic acid over a period of 2.5 hours.Completion is monitored, e.g., by TLC; if the starting materialcontinues to be present, temperature is increased to 50° C. untilcompletion. The corresponding, optionally substituted quinazolinone ofFormula 105 is isolated and purified.

[0076] Preparation of Formula 106

[0077] Referring to Reaction Scheme 1, Step 4, to 1.5 molar equivalentsof sodium azide in an inert organic solvent (such as DMF) is slowlyadded 1 molar equivalent of a compound of Formula 105. The reactiontakes place with agitation at a temperature of 40° C. over a period of 3to 10 hours. Completion is monitored, e.g., by TLC. The corresponding,optionally substituted quinazolinone azide of Formula 106 is isolatedand purified.

[0078] Preparation of Formula 107

[0079] Referring to Reaction Scheme 1, Step 5, to a solution oftriphenylphosphine dissolved in an inert organic solvent (such as THF)is added an azide of Formula 106, portionwise over about 15 minutes. Thereaction takes place with agitation, maintaining the temperature at 20°C. over a period of 5 minutes to 1 hour. The reaction mixture isacidified, solvents removed followed by conventional work up to give thehydrochloride salt of the corresponding, optionally substitutedquinazolinone of Formula 107, which is isolated and purified in theusual manner.

[0080] Preparation of Formula 107a

[0081] In certain compounds of the invention, particularstereoconfiguration can be preferred for the R² substituent, such as the(R) isomer, which can be obtained, e.g., as illustrated in optional Step5a of Reaction Scheme 1. An amine of Formula 107 is dissolved in aninert organic solvent (such as IPA) and warmed to 60° C. In a separatevessel, a resolving agent (such as dibenzoyl-D-tartaric acid) isdissolved, preferably in the same warm solvent, and then quickly added(with agitation) to the warm amine solution. The reaction mixture isleft to crystallize by cooling to room temperature over 16 hours undercontinuing agitation. The desired isomer, e.g., the (R) isomerillustrated as Formula 107a, is isolated and purified in the usualmanner.

[0082] Synthesis of Compounds of Formula I

[0083] The quinazolinone derivative of Formula II can be converted tocompounds of Formula I(a), I(b), I(c), or I(d) as described in theReaction Schemes below and as shown in the figures. See, also, PCT WO01/30768.

[0084] Preraration of Formula 203

[0085] Refering to Reaction Scheme 2, Step 1, to a solution of acompound of Formula 107 is added successively a slight excess(preferably about 1.2 equivalents) of an aldehyde comprising R₄ (i.e., acompound having the formula R₄CHO where R₄CH₂— is equivalent to R₄ andR₄ is as described above or is a protected precursor to such asubstituent, e.g., (3-oxo-propyl)-carbamic acid tert-butyl ester) and areducing agent such as sodium triacetoxyborohydride. The resultingmixture is stirred for several hours. The product, a compound of Formula203 is isolated and purified.

[0086] Preparation of Formula 205

[0087] Referring to Reaction Scheme 2, Step 2, to a solution of acompound of Formula 203 and an amine base such as diisopropylethylaminein a nonpolar, aprotic solvent such as dichloromethane is added an R₃acyl chloride (such as Cl—C(O)—R₃ where R₃ is as described above). Theresulting solution is stirred under nitrogen at room temperature forseveral hours. The product, a compound of Formula 205 is isolated andpurified.

[0088] Preparation of Formula 207

[0089] Optionally, any protecting groups on compounds of Formula 205 arethen removed. For example, if R₄ comprises a protected amine wherein theprotecting group is a Boc group, the Boc group can be removed bytreatment of the compound of Formula 205 with an acid such astrifluoroacetic acid in a nonpolar, aprotic solvent such asdichloromethane, while maintaining the reaction at about roomtemperature. The reaction is monitored e.g., by TLC. Upon completion,the product, a compound of Formula 207 is isolated and purified.

[0090] Referring to Reaction Scheme 3, to a solution of a compound ofFormula 203 and an amine base such as diisopropylethylamine in anonpolar, aprotic solvent such as dichloromethane is added a compoundhaving the formula Cl—S(O)₂—R_(3a) or O—(S(O)₂—R_(3a))₂ where R_(3a) isas described above. The resulting solution is stirred under nitrogen atroom temperature for several hours. The product, a compound of Formula303 is isolated and purified.

[0091] Referring to Reaction Scheme 4, to a solution of a compound ofFormula 203 and an amine base such as diisopropylethylamine in anonpolar, aprotic solvent such as dichloromethane is added a compoundhaving the formula Cl—CH₂—R_(3b) where R_(3b) is as described above. Theresulting solution is stirred under nitrogen at room temperature or withheat for several hours. The product, a compound of Formula 403 isisolated and purified.

[0092] Referring to Reaction Scheme 5, a compound of Formula 203 isreacted with a slight excess of a compound of the formula R₁₅O(CO)Cl inthe presence of a base such as triethylamine in a nonpolar, aproticsolvent such as dichloromethane. The product, a compound of Formula 503is isolated and purified.

[0093] Referring to Reaction Scheme 6, a compound of Formula 203 istreated with a slight excess of an isocyanate R₁₅—N═C═O in the presenceof a base, such as triethylamine, in a nonpolar, aprotic solvent, suchas dichloromethane. The product, a compound of Formula 603, is isolatedand purified.

EXAMPLES Abbreviations and Definitions

[0094] The following examples are given to enable those skilled in theart to more clearly understand and to practice the present invention.They should not be considered as limiting the scope of the invention,but merely as being illustrative and representative thereof.

[0095] The following abbreviations and terms have the indicated meaningsthroughout:

[0096] Ac=acetyl

[0097] Boc=t-butyloxy carbonyl

[0098] Bu=butyl

[0099] c-=cyclo

[0100] CBZ=carbobenzoxy=benzyloxycarbonyl

[0101] DBU=diazabicyclo[5.4.0]undec-7-ene

[0102] DCM=dichloromethane=methylene chloride=CH₂Cl₂

[0103] DCE=dichloroethylene

[0104] DEAD=diethyl azodicarboxylate

[0105] DIC=diisopropylcarbodiimide

[0106] DIEA=N,N-diisopropylethyl amine

[0107] DMAP=4-N,N-dimethylaminopyridine

[0108] DMF=N,N-dimethylformamide

[0109] DMSO=dimethyl sulfoxide

[0110] DVB=1,4-divinylbenzene

[0111] EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline

[0112] Et=ethyl

[0113] Fmoc=9-fluorenylmethoxycarbonyl

[0114] GC=gas chromatography

[0115] HATU=O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

[0116] HMDS=hexamethyldisilazane

[0117] HOAc=acetic acid

[0118] HOBt=hydroxybenzotriazole

[0119] Me=methyl

[0120] mesyl=methanesulfonyl

[0121] MTBE=methyl t-butyl ether

[0122] NMO=N-methylmorpholine oxide

[0123] PEG=polyethylene glycol

[0124] Ph=phenyl

[0125] PhOH=phenol

[0126] PfP=pentafluorophenol

[0127] PPTS=pyridinium p-toluenesulfonate

[0128] Py=pyridine

[0129] PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate

[0130] rt=room temperature

[0131] sat=d=saturated

[0132] s-=secondary

[0133] t-=tertiary

[0134] TBDMS=t-butyldimethylsilyl

[0135] TES=triethylsilane

[0136] TFA=trifluoroacetic acid

[0137] THF=tetrahydrofuran

[0138] TMOF=trimethyl orthoformate

[0139] TMS=trimethylsilyl

[0140] tosyl=p-toluenesulfonyl

[0141] Trt=triphenylmethyl

Example 1 Synthesis of Compounds

[0142] The general synthesis is shown in FIGS. 1 and 2 and is describedfurther above.

[0143] Step 1: N-butyryl Anthranilic Acid.

[0144] To a three-necked, 500 mL round-bottom flask equipped with athermometer, dropping funnel, and an efficient magnetic stir bar, wasadded anthranilic acid (1) (0.5 mole, 68.5 g) and dimethyl formamide(250 mL). To this solution was added butyryl chloride (0.55 mole, 57.1mL) dropwise at such a rate that the temperature of the mixture did notrise above 40° C. The suspension was stirred vigorously at roomtemperature for at least an additional 3 h. The mixture was poured intowater (2000 mL) and stirred for another 1 h. The precipitated productwas collected by filtration, washed with cold water, and dried underreduced pressure over P₂O₅, yielding compound 2 (67.3 g, 65%).

[0145] Step 2: 2-Propyl-3,1-[4H]benzoxazin-4-one.

[0146] Compound 2 (51.8 g, 0.25 mole) was dissolved in acetic anhydride(180 mL) in a 500 mL round-bottom flask equipped with a magnetic stirbar, a Claisen-distillation head (with vacuum inlet) and a thermometer.The flask was placed in an oil bath and slowly heated to 170-180° C.with vigorous stirring. The acetic acid produced was slowly distilledoff under atmospheric pressure. Monitoring the head temperature of thedistillation unit was used to follow the progress of the transformation.The reaction mixture was then cooled to 60° C. and the excess of aceticanhydride removed by distillation under reduced pressure (ca. 20 mm Hg).The residue was afterward cooled and the product crystallized. Theproduct was triturated with n-hexane (75 mL) and isolated by filtrationto yield 2-propyl-3,1-[4H]benzoxazin-4-one (3) (29.3 g, 62%). The aboveprocedure gave compound 3 sufficiently pure to use directly in the nextstep.

[0147] Step 3: 2-Propyl-3-benzylquinazolin4-one.

[0148] Compound 3 (28.4 g, 0.15 mole) and benzylamine (17.5 mL, 0.16mole) were refluxed in chloroform (50 ml) in a one-neck 250 mLround-bottom flask for 6 h. After complete consumption of compound 3,the chloroform was evaporated under reduced pressure. Ethylene glycol(100 mL) and NaOH pellets (0.60 g) were added to the residue and theflask equipped with a Claisen-distillation head and a magnetic stir bar.The flask was immersed in an oil bath and reheated to 130-140° C. bathtemperature with vigorous stirring and maintained there for 5 h whilethe water produced was removed by distillation. After completion of thereaction, the clear solution was allowed to cool to room temperature andkept overnight to precipitate the product. The pH of the suspension wasadjusted to 7-8 by adding 3% aq. HCl, the crystals were filtered off andwashed with cold water, and then recrystallized from isopropanol (oralternatively from acetone) to provide the compound,2-propyl-3-benzylquinazolin-4-one (compound 4) (28.0 g, 67%).

[0149] Step 4: 2-(1′-bromopropyl)-3-benzylquinazolin-4-one.

[0150] To a three-neck 250 mL round-bottom flask equipped with athermometer, dropping funnel, and efficient magnetic stir bar was addedcompound 4 (27.8 g, 0. 10 mole), anhydrous sodium acetate (10.0 g) andglacial acetic acid (130 mL). Bromine (16.0 g, 0.10 mole) dissolved inacetic acid (10 mL) was added dropwise to the above solution at 40 ° C.for 1-2 h. After addition was complete, the mixture was poured intowater (1500 mL) and stirred for 1-2 h at room temperature. Theprecipitated product, 2-(1′-bromopropyl)-3-benzylquinazolin-4-one (5)was isolated by filtration, washed with warm water to remove traces ofacetic acid, and rinsed with a small amount of isopropanol. Dryingyielded compound 5 (33.0 g, 92%).

[0151] Step 5:2-[1′-(N,N-dimethylethylenediamino)propyl]-3-benzylquinazolin-4-one.

[0152] Compound 5 (10.7 g, 0.03 mole) and N,N-dimethylethylenediamine(6.6 mL, 0.06 mole) were dissolved in abs. ethanol (60 mL) and heated atreflux for 6 h. After completion of the reaction, the solvent wasevaporated under reduced pressure. The residue was dissolved indichloromethane (150 mL) and washed with 3% aq. NaOH solution (ca. 10-20mL). The organic layer was dried over MgSO₄ and evaporated to drynessunder reduced pressure. The remaining oily product was purified by flashchromatography on a short silica gel pad using an eluent ofCHCl₃—MeOH-aq.NH₃, 90:10:0.1, to give the desired compound (5),2-[1′-(N,N-dimethylethylenediamino)propyl]-3-benzylquinazolin-4-one (6)(6.0 g, 55%).

[0153] Step 6:2-[1′-(N-4-fluorobenzoyl)-(N,N-dimethylethylenediamino)propyl]-3-benzylquinazolin4-one.

[0154] A stock solution of compound 5 (1.822 g, 5.0 mmol) was preparedin HPLC grade CHCl₃ (0.5 mL). A stock solution of p-fluorobenzoylchloride (160.2 mg, 1 mmol) in HPLC grade 1,2-dichloroethane (2.0 mL)was prepared in a 2.0 mL volumetric flask. A third solution oftriethylamine (2.0 mL of 0.5 M) was prepared in HPLC grade1,2-dichlorethane. A 100 μL aliquot of each solution was pipetted into aglass reaction vessel using a Beckman Biomet 2000 automated liquiddispenser. The reaction mixture was shaken using a mechanical shaker,sonicated in an ultrasonic water bath, and then incubated overnight atroom temperature. The mixture was diluted in CHCl₃ (300 μL) and washedwith 5% aqueous NaHCO₃ and water. The solvent was removed in vacuo toprovide compound 6 (65%). The purity of the compound was analyzed by TLCeluted with CH₂Cl₂-ethanol-concentrated aqueous NH₃, 100:10:1.

Example 2

[0155] The following two compounds were synthesized as singleenantiomers by the route shown in FIG. 3.

Example 3 Racemization Method

[0156] The S-isomer of the compound shown in FIG. 4, wherein R₁ isbenzyl; R₂ is isopropyl; R₅, R₆, and R₈ are hydrogen; and R₇ is chloro,(490 mg, 1.44 mmol) and sodium ethoxide (0.535 mL of a 21% by weightsolution in denatured alcohol containing 5% toluene; 1.64 mmol) weredissolved in abs. ethanol (2.5 mL) and heated at reflux for 36 h. Aftercompletion of the reaction, the solvent was evaporated under reducedpressure. The residue was dissolved in dichloromethane and washed with2N aq. HCl solution which was added dropwise until the solution had a pHof about 7. The organic layer was dried over Na₂SO₄ and evaporated todryness under reduced pressure. The remaining product (478 mg, 86% pureby NMR) comprised a 1:1.1 mixture of the R- and S-isomers as shown bychiral liquid chromatography.

[0157] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. All patents and publications cited above arehereby incorporated by reference.

1-13. (canceled)
 14. A method for making an enantiomer, or anenantiomerically enriched mixture of a compound of the formula

wherein said method comprises the steps of: contacting an enantiomer, oran enantiomerically enriched mixture of a starting compound of formula

 with an alkali alkoxide in a C₁-C₆ primary alcohol at a selectedracemization reaction temperature whereby said enantiomer orenantiomerically enriched mixture is racemized to yield a racemicmixture; isolating the racemic mixture; subjecting said racemic mixtureto an optical resolution process whereby the racemic mixture isseparated into its corresponding stereoisomers; and converting desiredstereoisomer to said compound using an acid chloride of the formulaR₃—C(O)—Cl wherein R₁ is selected from the group consisting of hydrogen,alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl,substituted aryl, substituted alkylaryl, substituted heteroaryl, andsubstituted alkylheteroaryl; R₂ and R_(2′) are independently selectedfrom the group consisting of alkyl, oxaalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl,substituted alkylaryl, substituted heteroaryl, and substitutedalkylheteroaryl; R₃ is selected from the group consisting of hydrogen,alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl,substituted aryl, substituted aralkyl, substituted heteroaryl,substituted heteroaralkyl, oxaalkyl, oxaaralkyl, substituted oxaaralkyl,R₁₅O— and R₁₅—NH—; R₄ is selected from the group consisting of hydrogen,alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl,substituted aryl, substituted aralkyl, substituted heteroaryl,substituted heteroaralkyl, and R₁₆-alkylene-; R₅, R₆, R₇, R₈ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, halogen, fluoralkyl, nitro, dialkylamino, alkylsulfonyl,alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio,carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl; R₁₅ isselected from the group consisting of alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl,substituted heteroaryl, and substituted heteroaralkyl; and R₁₆ isselected from the group consisting of alkoxy, amino, alkylamino,dialkylamino, N-heterocyclyl and substituted heterocyclyl.
 15. Themethod of claim 14, wherein the C₁-C₆ primary alcohol is ethanol. 16.The method of claim 14, wherein the alkali alkoxide is a sodium orpotassium alkoxide.
 17. The method of claim 14, wherein the alkalialkoxide is sodium ethoxide.
 18. The method of claim 14, wherein theracemization reaction temperature is less than 200° C.
 19. The method ofclaim 14, wherein the racemization reaction temperature is less than100° C.
 20. The method of claim 14, wherein the racemization reactiontemperature is at the boiling point of the reaction mixture.
 21. Themethod of claim 14, wherein the enantiomer has an R-configuration. 22.The method of claim 14, wherein the enantiomer has an S-configuration.23. The method of claim 14, wherein the alkali alkoxide is derived froman alkali metal and a C₁-C₆ primary alcohol.
 24. The method of claim 23,wherein the C₁-C₆ primary alcohol is methanol or ethanol.